The illicit use of cocaine continues to be a significant social problem. Although some of the chronic effects of psychostimulants have been well characterized, the neurochemical adaptations that occur in brain as a result of chronic drug use have not yet been elucidated. These experiments will characterize the effects of biogenic amine transporter blockade on receptors and receptor coupling to G-proteins in brain, which will provide further insight into biogenic amine systems. Specifically, the objectives of this project are to test the following hypotheses: 1) Long-term blockade of biogenic monoamine transporters desensitizes biogenic amine receptor/G-protein coupling in specific brain regions, 2) chronic treatment with long acting biogenic amine transport blockers produces a long-term blockade of biogenic amine transporters, 3) receptor/G-protein desensitization after chronic WF-23 treatment may result in downregulation of biogenic amine receptors, and 4) chronic treatment with WF-23 or cocaine may produce changes in receptor reserve for D2 receptors. Investigation of the neuronal mechanisms underlying chronic transporter blockade will provide insight into drug abuse and potentially provide the information necessary to create better treatment programs for psychostimulant abuse.